Oxygenated n-benzoyl-n,2,3,3-tetramethyl-exo-2-norbornanamines

ABSTRACT

1. A COMPOUND OF THE FORMULA A, B, C OR D:   2-(H3C-N(-R) -),2,3,3-TRI(H3C-),6-R-NORBORANE A   2-(H3C-N(-R)-),2,3,3-TRI(H3C-),7-R2-NORBORANE B   2-(H3C-N(-R)-),2,3,3-TRI(H3C-),6-(O=)-NORBORANE C   2-(H3C-N(-R)-),2,3,3-TRI(H3C-),7-(O=)-NORBORANE D   WHEREIN R IS BENZOYL AND R1 AND R2 ARE EACH HYDROXY OR METHOXY.

3,847,982 OXYGENATED N-BENZOYL-N,2,3,3-TETRA-METHYL-EXO-Z-NORBORNANAMINES Milton E. Herr, Kalamazoo, Herbert C.Murphy, Hickory Corners, and Gunther S. Fonken, Charleston Township,Kalamazoo County, Mich., assiguors to The Upjohn Company, Kalamazoo,Mich.

No Drawing. Original application July 15, 1970, Ser. No. 55,272, nowPatent No. 3,717,650. Divided and this application Nov. 24, 1972, Ser.No. 309,413

Int. Cl. C07c 103/22 US. Cl. 260558 R 12 Claims ABSTRACT OF THEDISCLOSURE This invention relates to a novel microbiological process forthe oxygenation of N-benzoyl-N,2,3,3-tetramethyl-ex- 2-norbornanamine toobtain N-benzoyl-exo-6-hydroxy- N,2,3,3-tetramethyl-exo-2-norbornanamineand N-benzoyltrans 7 hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine,each of which are chemically converted to novel derivatives. These novelbioconversion products and their derivatives are active hypotensiveagents and central nervous system stimulants.

This is a division of application Ser. No. 55,272, filed July 15, 1970,now US. Pat. 3,717,650.

SUMMARY OF THE INVENTION The novel compounds of this invention areillustratively represented by the following structural formulae:

wherein R is hydrogen, benzyl or benzoyl and R and R are each hydroxy,methoxy or acyloxy; and the pharmacologically acceptable acid additionsalts of the basic compounds of formulae A, B, C and D above, wherein Ris hydrogen or benzyl.

In this application the wavy lines (1) appearing at the 6-position inthe structural formula is indicative of compounds having the 6-exoconfiguration, the G-endo configuration and mixtures thereof and thewavy line appearing at the 7-position of the structural formula isindicative of compounds having the 7-cis configuration, the 7-zransconfiguration and mixtures thereof. The 7-cis and 7-trans configurationsare relative to the Z-methylamino group.

The novel compounds of this invention represented by formulae A, B, Cand D, above, and the pharmacologically acceptable acid addition saltsof the basic compounds of formulae A, B, C and D, wherein R is hydrogenor benzyl, have ganglionic blocking activity and are useful hypotensiveagents; they are also central nervous system stimulants. As hypotensiveagents they are useful for lowering blood pressure, and as centralnervous system stimulants they are mood elevators and psychic energizerswhich are useful in the treatment of mental health conditions.

"United States Patent Oficc 3,847,982 Patented Nov. 12, 1974 The novelcompounds of this invention and the pharmacologically acceptable acidaddition salts thereof are useful in the treatment of animals and:birds, and are particularly useful in the treatment of humans andvaluable domestic animals. They can be administered as activeingredients in conventional pharmaceutical forms such as tablets,capsules, elixirs, injectable solution and suspen- SlOIlS.

The novel compounds of this invention, represented by formulae A, B, Cand D, above, are prepared by subjectingN-benzoyl-N,2,3,3-tetramethyl-exo-Z-norbornanamine to the oxygenatingactivity of the microorganism Sporofrichum sulfurescens to obtainN-benzoyl-exo-6-hydroxy- N,2,3,3-tetramethyl-ex0-2-norbornanamine andN-benzoyltrans 7 hydroxy N,2,3,B-tetramethyl-exo-2-norbornan amine, eachof which are converted to the other novel compounds of this invention inaccordance with methods known in the art.

DETAILED DESCRIPTION OF THE INVENTION The microbiological process ofthis invention is represented by the following reaction scheme:

CH3 0 '--t \CH3 (I cu, cn, o HQ H cHs CH; CH3

CH: u l I CH: ll I l The microbiological process of this inventioncomprises subjecting N benzoyl-N-2,3,3-tetramethyl-exo-Z-norbornanamine(I) to the oxygenating activity of the microorganism Sporotrichumsulfurescens, to obtain N-benzoylexo -6 hydroxy N,2,3,3tetramethyl-exo-Z-norbornanamine II) andN-benzoyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (HI).

The genus Sporotrichum belongs to the family Moniliaceae of the orderMoniliales of the class Deuteromycetes. The typical strain preferred forthe practice of this invention is Sporotrichum sulfurescens, CollectionNo. ATCC 7159; available from the American Type Culture Collection(ATCC), Washington, DC. It is to be understood that other strains ofthese microorganisms are suitable for the practice of this invention.

The starting material (I) for the microbiological process of thisinvention is prepared by treatingN,2,3,3-tetramethyl-exo-Z-norbornanamine, hydrochloride (mecamylamine,hydrochloride) with dilute sodium hydroxide followed by treatment withbenzoyl chloride in accordance with Preparation 1, herein, to obtainN-benzoyl-N,2,3,3- tetramethyl-ex0-2-n0rbornanamine (I).

The operational conditions and reaction procedures for bioconversionprocess of this invention are advantageously those known in the art ofbioconversion as illustrated in Murray et al., US. Pats. 2,602,769 and2,735,- 800, utilizing the oxygenating activity of the microorgamsm.

Sporotrichum sulfurescens In the practice of this invention, thebioconversion can be effected by a growing or resting culture of themicroorganism or by spores, washed cells or enzymes of themicroorganism.

Culture of the microorganism for the purpose and practice of thisinvention is in or on a medium favorable to its development. Sources ofnitrogen and carbon should be present in the culture medium and anadequate sterile air supply should be 'r'haintained during theconversion, for example, by the conventional techniques of exposing alarge surface of the medium or by passing air through a submergedculture.

Nitrogen in assimilable form can be provided by sources normallyemployed in such processes, such as corn steep liquor, soybean meal,yeast extracts, peptone, soluble or insoluble vegetable or animalprotein, lactalbumin, casein, Whey, distillers solubles, amino acids,nitrates and ammonium compounds, such as ammonium tartrate, nitrate,sulfate and the like.

Available carbon can also be provided by sources normally used inbioconversions such as carbohydrates, e.g., glucose, fructose, sucrose,lactose, maltose, dextrines, starches: meat extracts, peptones, aminoacids, proteins, fatty acids, glycerol, whey and the like. Thesematerials may be used either in a purified state or as concentrates suchas whey concentrate, corn steep liquor, grain mashes, and the like, oras mixtures of the above. Many of the above sources of carbon can alsoserve as a source of nitrogen.

The medium can desirably have a pH before inoculation of between about 4to about 7 though a higher or lower pH can be used. A temperaturebetween about 25 to 32 C. is preferred for growth of the microorganismbut higher or lower temperatures within a relatively wide range aresuitable.

The substrate (I) can be added to the culture during the growth periodof the microorganism as a single feed or by gradual addition during theconversion period, or it can be added to the medium before or aftersterilization or inoculation making appropriate adjustments for effectsof pH and/or temperature upon the stability of the substrate. Thepreferred, but not limiting, range of concentration of the substrate inthe culture medium is about 0.1 to 10 grams per liter. The substrate isadded to the medium in any suitable manner, especially one whichpromotes a large surface contact of the substrate to the oxidizingactivity of the microorganism, for example by dissolving the substratein an organic solvent and mixing the solution thoroughly with the mediumor by adding to the medium finely comminuted particles of the substrate,e.g., micronized particles, preferably 90% by weight smaller thanmicrons, either as a dry powder or, preferably for mechanical reasons,as an aqueous suspension. In preparing the aqueous suspension, the useof dispersing or suspending agents is advantageous. Dispersing agentscan also be added to the medium.

The temperature during the fermentation can be the same as that foundsuitable for growth of the microorganism. It need be maintained onlywithin such range as supports life, active growth or the enzyme activityof the microorganism, the range of 20 to C. is preferred. A pH of about4 to 8 is generally preferred for growth of the microorganism during thebioconversion. Aeration can be effected by surface culture or preferablyunder submerged fermentation conditions, in accordance with methods wellknown in the art. The time required for oxygenation by the enzymaticsystem of the microorganism employed can vary considerably. The range ofabout 2 to 120 hours is practical but not limiting; 72 hours isgenerally satisfactory. The progress of the bioconversion and itscompletion are conveniently determined by paperstrip chromatography,vapor-phase chromatography, or

4 thin-film chromatography [Haftman, Chromatography (1961) ReinholdPublishing Co., New York, N.Y.].

Alternatively, the oxygenation of the selected substrate can be effectedunder aerobic conditions by subjecting it to the oxygenating action ofoxygenating enzymes isolated from the microorganism, to the action ofspores of the microorganism, and to the action of isolated cells of themicroorganism. Isolated enzyme preparations can be prepared inaccordance with the general procedure disclosed by Zuidweg et al.,Biochim. Biophy. Acts, 58, 131-133 (1962). Oxygenation can be effectedwith spores in accordance with the general process disclosed in US.Pats. 3,031,379 and 3,031,382. The separation of washed cells from thefermentation medium is well known in the art, see for example, U.S. Pat.2,831,789.

The term oxygenating activity as used throughout this specificationmeans the enzymatic action of a growing or resting culture of themicroorganism or of spores, washed cells or isolated enzymes of themicroorganism, which effects introduction of oxygen in the molecule ofthe substrate under aerobic fermentation conditions.

After completion of the fermentation, the resulting oxygenated products(II) and (III) are recovered from the fermentation beer by conventionalmethods. For example, the whole beer can be extracted with aWater-immiscible organic solvent such as methylene chloride, chloroform,carbon tetrachloride, ethylene chloride, trichloroethylene, ether, amylacetate, benzene, and the like or the beer and mycelia can be separatedby conventional methods such as centrifugation or filtration, and thenseparately extracted with suitable solvents. The mycelia can be extracted with either water-miscible or water-immiscible solvents or incases where little or no product is contained in the mycelium, it can bemerely washed with water and the wash water added to the beer filtrate.The beer, free of mycelia, can then be extracted with water-immisciblesolvents such as those listed above. The extracts are combined, driedover a drying agent such as anhydrous sodium sulfate, and the solventremoved by conventional methods such as evaporation or distillation atatmospheric or reduced pressure.

Alternatively, the products can be adsorbed from the beer on granularcharcoal and the products eluted with a polar organic solvent such asmethanol, ethanol, acetone, ethyl acetate, and the like.

The oxygenated products (II) and (III) obtained by either the extractionor elution procedures can be isolated and further purified byconventional methods, e.g., chromatography and/or crystallization, andthe like.

The compounds of formulae (II) and (Ill) are converted to the othercompounds of this invention in accordance with the following reactionschemes:

SCHEME 1 (vn) (v) mm on, --cn.

CH CH3 cu, (v: l (VI SCHEME 2 XH; (IX

CH3 CH3 (Xll nus m 6H:

CH3 CH: e

\Ha (xm) m SCHEME3 CH3 CH,

N-R; H0

KX HQ CH 3 cu, (x|v) (xv) CHa a N-R;

(XVII) wherein R is hydrogen or benzyl.

6 SCHEME 4 CH3 (XXI l SCHEMES 1 AND 2 The compounds (II) and (HI),obtained from the bioconversion process of this invention are oxidizedto obtain the corresponding keto compounds of formulae (IV) and (IX)respectively, in accordance with methods known in the art for oxidizingsecondary hydroxy groups to ketones, for example, Fieser and Fieser,Natural Products Related to Phenanthrene, 3rd ed., pp. 127-129,Rheinhold Publishing Corporation, New York, NY. Thus, the selectedcompound (II) or (111) is dissolved in an inert organic solvent such asacetone, benzene, methylene chloride, t-butanol, and the like, and thenoxidized with aqueous chromic acid, e.g., Jones reagent, to convert thehydroxy group to keto. The corresponding keto compounds IV) and (IX)thus obtained, are recovered from the reaction mixture and purified byconventional methods. For example, extraction with an organic solvent,e.g., methylene chloride followed by recrystallization from a suitableorganic solvent, e.g. acetone, benzene, methylene chloride, hexanes,mixtures thereof, and the like.

The keto compounds (IV) and (IX) thus obtained are selectively reducedat the ring attached keto group in accordance with methods well known inthe art, for example, using sodium or potassium borohydride to obtainthe corresponding enda-fi-hydroxy and cis-7-hydroxy compounds offormulae (V) and (X), respectively, which are separated from thereaction mixture and purified by conventional methods such ascrystallization, chromatography and the like. Alternatively, thecompounds of formulae (IV) and ([IX) can also be reduced at both thering keto group and the amido group by known methods, for example, usinglithium aluminum hydride to obtain the corresponding benzylamines offormulae (VI) and (XI), respectively.

The hydroxy benzamides of formulae (II), (V), (III) and (X) are reducedin accordance with methods known in the art for reducing amides toamines to obtain the corresponding hydroxy benzylamines of formulae(VII),

(VI), (XII) and (XI) respectively. The reduction is preferably carriedout using lithium aluminum hydride as the reducing agent. The reductionreaction is carried out in the presence of an inert organic solvent suchas ether, tetrahydrofuran, benzene, diglyme, combinations thereof andthe like. The reduction reaction is preferably conducted at refluxtemperature and a period of about 1 to about 4 hours depending on thesolvent employed is generally sufiicient for completion of the reaction.The hydroxylamines thus obtained are recovered as the free bases byconventional methods and are purified if desired by distillation.Alternatively, the hydroxybenzylatnines can be recovered and purified bypreparation of the acid addition salts thereof in accordance withmethods hereinafter described. I

The hydroxybenzylamines of formulae (VII) and (VI) and formulae (XII)and (XI) thus obtained, are converted to the corresponding norbornaminesof formulae (VIII) and (XIII) respectively by catalytic hydrogenolysisin accordance with methods known in the art [Or- I ganic Reaction, vol.VII, p. 277, John Wiley & Sons, Inc, New York (1953)}, for example usinghydrogen and palladium on carbon catalyst. The compounds of formulae(VIII) and (XIII) are recovered from the reaction mixture byconventional methods, such as removal of catalyst by filtration,extraction with a suitable organic solvent followed by chromatographyand/or'crystaliization. Alternatively the compounds of formulae (VIII)and (XIII) are recovered as the acid addition salts as hereinafterdescribed.

SCHEME 3 The 6-hydroxy compounds of formulae (VI), (VII) and (VIII)represented collectively by formula (XIV) and the 7-hydroxy compounds offormulae (XI), (XII) and (XIII) represented collectively by formula (XV)are oxidized using an Oppenauer oxidation, for example, using a ketone,such as acetone or cyclohexanone and an aluminum alkoxide, such asaluminum isopropoxide in an organic solvent, e.g., benzene or toluene toobtain the corresponding ketoamines of formulae (XVI) and (XVII),respectively, The keto-amines are recovered from the reaction mixture byconventional methods, for example, first neutralizing or acidifying thereaction mixture with a mineral acid, e.g., hydrochloric acid,extracting the mixture thus obtained with a suitable organic solvent,e.g., benzene, toluene, ether, methylene chloride and the like, toremove organic impurities. The aqueous layer is then made basic, forexample, with sodium or potassium hydroxide and product is extractedwith ether or other suitable organic solvent and the solvent is removedby evaporation or distillation. Alternatively, the keto-amines offormulae (XVI) and XVII) can be recovered as their acid addition saltsas hereinafter described.

Alternatively the compounds of formulae (XVI) and (XVII) wherein R ishydrogen are prepared from the corresponding compounds of formulae (XVI)and (XVII), respectively, wherein R is benzyl, by catalytichydrogenolysis as hereintofore described.

SCHEME 4 The compounds of formulae (II) and (V), representedcollectively by formula XVIII and the compounds of formulae (III) and(X), represented collectively by formula (XIX) are converted to theircorresponding methoxy derivatives of formulae (XX) and (XXI),respectively, in accordance with methods known in the art. The selectedcompound of formulae (XVIII) or (XIX) is treated with aluminumisopropoxide and diazomethane using the method of A. Popelak and G.Lettenbauer, Arch. Pharmay., 295, 427 (1962) to obtain the correspondingmethoxy compounds of formulae (XX) and (XXI), respectively, which areisolated and recovered from the reaction mixture by conventional methodssuch as chromatography and/or crystallization from a suitable solvent.

The compounds of formulae (XX) and (XXI) thus obtained are reduced tothe corresponding benzyl compounds of formulae (XXII) and (XXIII),respectively, with lithium aluminum hydride as hereintofore disclosedunder Schemes 1 and 2, above, for example, the reduction of compound(II) to compound (VII).

The compounds of formulae (XXII) and (XXIII) thus obtained are thensubjected to catalytic hydrogenolysis in accordance with the methodhereintofore disclosed to obtain the corresponding secondary amines offormulae (XXIV) and (XXV), respectively.

Acyl derivatives of the compounds of formulae (II), (III), (V), (VI),(VII), (VIII), (X), (XII) and (XIII) of this invention are prepared inaccordance with methods commonly used for preparing steroid acylates,for example by treating the selected hydroxy compound in pyridine withexcess acid anhydride or acid chloride at about room temperature for1-24 hours, or by heating the selected compound with an acid anhydridein the presence of an alkali earth carbonate such as calcium carbonate.Acylating agents which can be employed are for example the anhydridesand chlorides or organic carboxylic acids, preferably hydrocarboncarboxylic acids of 1 to 12 carbon atoms, inclusive, such as acetic,propionic, butyric, isobutyric, pivalic, valeric, isovaleric, caproic,caprylic, decanoic, dodecanoic, acrylic, crotonic, hexynoic, heptynoic,octynoic, cyclobutanecarboxylic, cyclopentenecarboxylic,cyclohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic,naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric,cinnamic, phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic,succinic, glutaric, dimethylglutaric, maleic, cyclophentylpropionic,p-toluenesulfonic acids, and the like.

The compound of formulae (VIII and (XIII) can in most instances beselectively acylated at either the 6- or 7-hydroxy group withoutconcommitantly forming the corresponding amides. If formation of theamide is a problem the 6- and 7-acrylates of the compounds of formulae(VIII) and (XIII) can be prepared by catalytic hydrogenolysis of thecorresponding acrylated benzylamines of formulae (VI), (VII), (XI) and(XII).

The free amines of formulae (VI), (VII), (VIII), (X), (XI), (XII),(XIII), (XVI), (XVII), (XXII), (XIII), (XXIV) and (XXV) of thisinvention can be converted by known methods to their pharmacologicallyacceptable acid addition salts by treating the selected amine with theappropriate acid. Acids which can be used are, for exam ple, sulfuric,hydrochloric, nitric, phosphoric, lactic, benzoic, methanesulfonic,p-toluenesulfonic, salicyclic, acetic, propionic, maleic, malic,tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, ascorbic andlike acids, in the presence of an inert solvent such as methanol,ethanol, diethyl ether, ethyl acetate, and the like.

The following preparation and exampes illustrate the best modecontemplated by the inventors for carrying out their invention, but arenot to be construed as limiting the scope thereof.

PREPARATION 1 N-benzoyl-N,2,3,3-tetramethyl-exo-Z-norbornanamine (1 Amixture of 78.0 g. of N,2,3,3-tetramethyl-ex0-2-norbornanaminehydrochloride, 600 ml. of 10% sodium hydroxide solution, and 48 ml. ofbenzoyl chloride is stirred in an ice bath for about 1 hr. and then atroom temperature for about 1 hour. After adding 36 ml. more of beamylchloride, the mixture is stirred for 24 hours, extracted with ether, theextract washed with water and dried over sodium sulfate. The solvent isremoved and the residue crystallized by dissolving in methanol andadding water. The solid is recovered, dried and recrystallized fromhexane; yield 98.0 g. of N-benzoyl-N,2,3,3-tetramethyl-exo-2-norbornanamine (I), m.p. 64-65 C.

9 EXAMPLE 1 N-benzoyl-ex-6-hydroxyN-2,3,3-tetramethyl-ex0-2-norbornanamine (II) A medium is prepared of 40 g. of cornsteep liquor(60% solids), g. of commercial dextrose diluted to 1 liter with tapwater and adjusted to a pH of between 4.8 and 5.0. One ml. of UCON LB625 (Union Carbide) is added as an antifoam agent. One hundred liters ofthis medium is sterilized and inoculated with 72-hour vegetative growthof Sporotrichum sulfurescens, ATCC 7159, and incubated at about 28 C.with aeration at about 5 l. per minute and stirring at about 300 r.p.m.After about 43 hours, or when a moderate to heavy growth of mycelium isapparent, 250 ml. of ULRAWET DS 30 (ARCO Chemical Co.) and a solution of12 g. of N-benzoyl-N-2,3,3-tetramethyl-exm2- norbornanamine (I) in about200 ml. of N,N-dimethylformamide is added to the fermentation. After anadditional 72-hour period of incubation 1500 g. of diatomaceous earth(Celite) is added and the beer and mycelium are separated by filtration.

The beer thus obtained, is extracted 4 times with l. of methylenechloride. The extracts are filtered, dried over sodium sulfate andevaporated to remove the solvent. The residue thus obtained is taken upin 300 ml. of methylene chloride and chromatographed over a columncontaining 600 g. of Florisil (synthetic magnesium silicate). The columnis eluted by the linear gradient method with 18 l. of Skellysolve Bhydrocarbons containing increasing proportions of acetone from 0 to 18%.Cuts of 325 ml. each are collected and the residues therefrom examinedby thin-layer chromatography (TLC) which showed the presence ofN-benzoyl-exo-6-hydroxy-N,2,3,3-tetramethylex0-2-norbornanamine (II) andN benzoyl-trans-7-hydroxy-N,2,3,3-tetramethyl exo 2 norbornamine (III).Those fractions containing N-benzoyl-exo-6-hyd.roxy-N-,2, 3,3tetramethyl-exo-Z-nonbornanamine are pooled and crystallized from etherto give 3.05 g. (21% yield) of N-benzoyl-exo-6-hydroxy-N-2,3,3tetramethyl-exo-Z-norbornanamine (1)), m.p. 178l80 C.; an analyticalsample recrystallized from methylene chloride-ether, m.p. 180- 182 C.

Analysis.Calcd. for C H NO C, 75.22; H, 8.77; N, 4.87. Found: C, 75.28;H, 8.86; N, 4.87.

EXAMPLE 2 N-benzoyl-6-keto-N,2,3,3-tetramethyl-exo 2 norbornanamine (IV)and N-benzoyl-7-keto-N,2,3,3-tetramethylexo-2-norbornanamine (]X) Thebioconversion and extraction procedures of Example 1, above, arerepeated using 120 l. of sterilized medium of the same composition; themicroorganism Spora- Irichum sulfurescens, ATCC 7159, and g. of the samesubstrate, N-benzoyl N,2,3,3 tetramethyl-exo-Z-norbornanamine (I). Thinlayer chromatographic analysis of the extract residues thus obtainedshows the presence of N-benz0yl-ex0-6-hydroxy N,2,3,3 tetramethyl-exo-Z-norbornanamine (II) and N-benzoyl-trans-7-hydroxy-N-2,3,3-tetramethyl-exo-Z-norbornanamine (III).

The residue extract obtained above, is dissolved in 500 ml. of acetoneand oxidized with 35.0 ml. of chromic acid solution (Jones reagent,prepared from 267 g. of chromic anhydride, 230 ml. of concentratedsulfuric acid and water sufficient to make 1 l.). The mixture is stirredfor five minutes; 10.0 ml. of isopropanol is added and the mixture isconcentrated under reduced pressure to about one-third volume, dilutedwith 500 ml. of water, and extracted several times with methylenechloride. The combined extracts are washed with water, dried over sodiumsulfate and concentrated to remove the solvent to obtain 30 g. of oil.The oil thus obtained is placed on a column containing 1500 g. ofFlorisil. The column is eluted in cuts of 1 1. each with 4 1. each ofSkellysolve B hexanes containing 5%, 8%, 11%, 14% and 17% acetone. Thefractions are examined by TLC and those containing predominatelyN-benzoyl-6-keto-N,2,3,3-tetramethyl-exo- 2-norbornanamine are combinedto give 7.62 g. (24% yield ofN-benzoyl-6-keto-N,2,3,S-tetramethyl-exo-Z-norbornanamine (IV); ananalytical sample, m.p. 82 C.

Analysis.-Calcd. for C H HO' C, 75.75; H, 8.12; N, 4.91. Found: C,76.05; H, 7.98; N, 4.85.

The fractions containing predominately N-benzoyl-7-keto-N-2,3,3-tetramethyl-exo-2-norbornanamine are combined and thesolvent removed to give 9.32 g. (29% yield) of N-benzoyl-7-keto N 2,3,3tetramethyl-exo-Z-norbornanamine (IX); an analytical sample of whichobtained by crystallization from acetone-Skellysolve B hexanes, m.p.l36138 C.

Analysis.-Calcd. for C I-I NO C, 75.75; H, 8.12; N, 4.91. Found: C,76.06; H, 7.94; N, 4.72.

EXAMPLE 3N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethylexo-2-norbornanamine (V) Asolution of 15 g. ofN-benzoyl-6-keto-N,2,3,3-tetramethyl-exo-2-norbornanamine (IV) in about250 ml. of methanol is stirred with 10.0 g. of sodium borohydride in 50ml. of water for about 16 hr. The mixture is chilled and carefullytreated with 50% aqueous acetic acid until pH 6. Most of the methanol isthen evaporated, the mixture is diluted with ml. of water, chilled, andthe solid product recovered by filtration, washed with water, and dried,yield, 14.84 g. of N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (V), m.p. 22.3-- 227 C.;recrystallized from methanol-water, m.p. 230- 231 C.

Analysis.Calcd. for C H NO C, 75.22; H, 8.77; N, 4.87. Found: C, 75.32;H, 9.04; N, 5.11.

EXAMPLE 4N-benzoyl-cis-7-hydroxy-N-2,3,3-tetramethylexo-2-norbornanamine (X)Following the procedure of Example 3, above a solution of 6.0 g. ofN-benzoyl-7-keto-N,2,3,3-tetramethylex0-2-norbornanarnine (V) in about100 ml. of methanol is treated with 5.0 g. of sodium borohydried in 25ml. of water to obtain 4.34 g. of N-benzoyl-cis-7-hydroxy-N-2,3,3-tetramethyl-exo-2-norbornanamine (X), m.p. 186-188 C.; an analyticalsample recrystallized from acetone-water, m.p. 186l87 C.

Analysis.Calcd. for C H NO C, 75.22; H, 8.77; N, 4.87. Found: C, 75.46;H, 8.96; N, 4.84.

EXAMPLE 5 N-benzyl exo 6 hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (VH), and the hydrochloride salt thereof Five grams ofN-benzoyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (II) in100 ml. of anhydrous tetrahydrofuran is added during 10 minutes withstirring to a mixture 5.0 g. of lithium aluminum hydride and 100 ml. ofether. The mixture is refluxed for 70 minutes, chilled in a cold bath at-10 C. and cautiously treated with 25 ml. of water while stirringvigorously. When the mixture is completely white, the inorganic solid isremoved by filtration and washed well with ether. The combined filtrateand wash are dried over magnesium sulfate and the solvent is evaporatedto yield 4.76 g. of N-benzyl-exo-6-hydroxy-N,2,3,3-tetramethyl exo2-norbornanamine (VII), as a colorless oil. For testing purposes and foranalysis this free base is dissolved in ether and converted to itshydrochloride salt by addition of a slight excess of ethereal HCl.Recrystallization from methanol-ether gives Nbenzyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine,hydrochloride, m.p. 164- 165 (dec.).

Analysis.-Calcd. for C H NOCI: C, 69.79; H, 9.11; CI, 11.44. Found. C,69.42; H, 8.94; Cl, 11.01.

'1 1 EXAMPLE 6 I 11 ;benzyl endo tihydroxy-N,2,3,3-tetramethyl-exo-2-norbornauamine (VI) and thehydrochloride salt thereof EXAMPLE 7 N benzyl-cis-7-hydroxy N,2,3,3tetramethyl-exo-Z-norbornanamine (XI) and the hydrochloride salt thereofEXAMPLE 8 Nbenzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-ex0-2-norbornanamine (XI) andthe hydrochloride salt thereof Following the procedure of Example 5,above, N-benzoyl-tmns-7-hydroxy N,2,3,3 tetramethyl-ex0-2-norbornanamine(III) is converted in nearly quantitative yield to obtainN-benzyl-trans-7-hydroxy-N,2,3,3-tetramethylex0-2-norbornanamine (XII),and N-benzyl-tmns-7-hydroxy-N,2,3,3-tetramethyl-ex0-2-norbornanaminehydrochloride.

EXAMPLE 9 Exo-6-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornan- :amine(VIII).and the hydrochloride salt thereof A solution of 4.0 g. ofN-benzoyl-exo-fi-hydroxy-N, 2,3,3 -tetramethyl exo Z-norborhanamiue(VII) is dissolved in about 30 ml. of ethanol; 0.75 g. of 10% palladiumon carbon is added and the mixture is shaken with hydrogen at about 45p.s.i.g. for about 16 hours or until the uptake of hydrogen is complete.The catalyst is removed by filtration and the filtrate is concentratedin vacuo to -give ex0-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine(VIII) as the free base. The free base thus obtained is dissolved inether and treated with a slight excess of ethereal hydrogen chloride toprecipitate the hydrochloride salt, which is recovered by filtration,washed with ether and dried to give 2.75 g. of ex0-6-hydroxyN,2,3,3-tetramethyI-exO-Z-norbornanamine, hydro- .chloride, m.p. 282 C.(dec.).

AnalysisF-Calcd. for C H NQ-HCI: C, 60.11; H, 10.09; Cl, 16.14. Found:C, 60.36; H, 10.16; Cl, 16.13.

EXAMPLE l0 Enda-fi-hydroxy-NJ,3,3-tetramethyl-exo-Z-norbornanamine(VIII) and the hydrochloride salt thereof The procedure of Example 9,above, is repeated using 4.0 g. of.N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethylexO-Z-norbornanamine (V) asthe starting material to obtain endo6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (VIII) which istreated with ethereal HCl to give 2.10 g. ofend0-6-hydroxy-N,2,3,3-tetramethylrexo- 2-norbornanamine, hydrochloride,mp. 244-247 C.

:, Analysis.-Calcd. for C H NO-HCl: C, 60.11; H,

10.09; Cl, 16.14. Found: C, 59.95; H, 10.26; Cl, 15.91.

12 EXAMPLE 11 Cis-7-hydroxy-N,2,3,3-tetramethyl-ex0-2-norbornanamiue(XIII) and the hydrochloride salt thereof The procedure of Example 9,above, is repeated using 4.0 g. ofN-benzyl-cis-7-hydroxy-N,2,3,3-tetramethylexo- 2-norbornanamine (XI) asthe starting material to obtain cis 7-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XIII) which istreated with ethereal HCl to give 2.30 g. of end0-6-hydroxyN,2,3,3-tetramethyl-ex0-2-norbornanamine, hydrochloride, mp. 270-275 C.

Analysis.Calcd. for C H NO-HCl: N, 16.14. Found: N, 6.81; Cl, 16.05.

EXAMPLE 12 Trans-7-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine(XIII) and the hydrochloride salt thereof The procedure of Example 9,above, is repeated using 4.0 g. ofN-benzoyl-trans-7-hydroxy-N,2,3,3-tetramethylexo-Z-norbornanamine (XII)as the starting material to obtain trans-7-l1ydroxy N,2,3,3tetramethyl-exo-Z-norbornanamine (XIII) andtrans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride.

EXAMPLE 13 N-benzyl-6-keto-N,2,3,3-tetramethyl-exo-Z-norbornanamine(XVI) and the hydrochloride salt thereof A solution of 10.0 g. ofN-benzyl-endo-6-hydroxy-N, 2,3,3-tetramethyl-exo-2-norbornanamine (XIV)in 600 ml. of toluene and 150 ml. of cyclohexanone is distilled toremove ml. of toluene. Aluminum isopropoxide (20.0 g.) is then added andthe mixture is heated at reflux for about 1 hour. The reaction mixtureis then cooled, poured into ice-water containing excess hydrochloricacid, stirred and the layers allowed to separate. The aqueous layer isfurther extracted with ether and then made basic by the addition of 50%aqueous sodium hydroxide solution. The resulting aqueous mixture isextracted with ether. The ether extract is washed with water and driedover magnesium sulfate. The dried ethersolution is evaporated to removethe solvent to giveN-benzyl-6-keto-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XVI) as thefree base. The free base thus obtained is dissolved in ether and treatedwith a slight excess of ethereal hydrogen chloride and the crystallineprecipitate thus obtained is recovered by filtration, washed with etherand dried to give N-ben-Zyl-6-keto-N,2,3,3-tetramethyl-exo-Z-norbornanamine, hydrochloride,which is further purified by recrystallization from methanol-ether.

Following the procedure of Example 13 other 6- and 7- hydroxy compoundsof this invention are likewise oxidized to give the corresponding ketocompounds, for example:

N-benzyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (XIV)to give N-benzyl-6-ket0-N,2, 3,3-tetramethyl-exo-2-norbornanamine (XVI)and the hydrochloride salt thereof;

N-benzyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanarnine (XV) togive N-benzyl-7-keto-N,2,3,3- tetramethyl-exo-Z-norbornanamine (XVII)and the hydrochloride salt thereof;

N-benzyl-trans-'I-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (XV)to give N-benzyl-7-keto-N,2,3,3- tetramethyl-exo-Z-norbornanamine (XVII)and the hydrochloride salt thereof;

exo-6-hydroxy-N,2,3,3-tetramethyl-exo 2 norbornanamine (XVI) to give 6keto N,2,3,3 tetramethylexo-2-norbornanamine (XVI) and the hydrochloridesalt thereof;

end0-6-hydroxy-N,2,3,3-tetramethyl-ex0 2 norbornanamine (XIV) to give6-keto-N,2,3,3-tetramethyl-N,2,3, 3,-tetramethyl-exo-Z-norbornananfine(XVI) and the hydrochloride thereof;

cis 7 hydroxy-N,2,3,3-tetramethyl-exo 2 norbornanamine (XV) to give7-keto-N,2,3,3-tetramethyl-exo-2 bornanamine (XVII) and thehydrochloride salt there of; and

trans 7 hydroxy-N,2,3,3-tetramethyl-ex-2-norbornanamine (XV) to give7-keto-N,2,3,3-tetramethyl-ex0-2- norbornanamine (XVII) and thehydrochloride salt thereof.

EXAMPLE 14 Ex0-6-methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XXIV)and the hydrochloride salt thereof A solution of 5.46 g. (0.02 mole) ofN-benzoyl-exo-6- hydroxy-N,2,3,3-tetramethyl-exo 2 norbornanamine(XVIII) in about 150 ml. of methylene chloride is treated with 2.5 g. ofaluminum isopropoxide and then with 100 ml. of a methylene chloridesolution of diazomethane (prepared from 265 ml. of methylene chloride,22.0 g. of N-methyl-N-nitro-N-nitrosoguanidine, and 70 ml. of 45%potassium hydroxide solution). After standing at room temperature forabout 3.5-4 hrs., 100 ml. more methylene chloride solution ofdiazomethane is added. The mixture is allowed to stand for about 22 hrs.The solution is washed with 100 ml. of water, 100 ml. of sulfuric acid,and twice with 50 ml. of water and dried over sodium sulfate. Themethylene chloride solution is chromatographed over Florisil, eluting bythe linear gradient method with 6 l. of solvent, Skellysolve B hexanescontaining increasing proportions of acetone. Cuts of 200 ml. each aretaken and the residues examined by TLC and infrared assays. The cutscontaining the desired product are combined to give 3.57 g. ofN-benzoyl-exo6-methoxy-N,2,3,3- tetramethyl-exo-Z-norbornanamine (XX)which is dissolved in about 50 ml. of ether and reduced with a solutionof 4.0 g. of LiAlHq, in 100 ml. of ether. The mixture, thus obtained isrefluxed for about 70 minutes, chilled in a cold bath at 10 andcautiously treated with 25 ml. of water while stirring vigorously. Whenthe mixture is completely White, the inorganic solid is removed byfiltration and washed well with ether. The combined filtrate and washare dried over magnesium sulfate and the solvent is evaporated to yield2.89 g. of N-benzyl-exo-6-methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XXII) as a white solid. Theproduct thus obtained, (2.89 g.) is dissolved in about 100 ml. ofethanol by warming and reduced with hydrogen and 0.5 g. of 10% palladiumon carbon catalyst at about 45 p.s.i.g. until the uptake of hydrogen iscomplete (about 16 hours). The catalyst is removed by filtration and thefiltrate is concentrated in vacuo to giveexo-6-methoxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (XXIV) as thefree base. The free base thus obtained is dissolved in ether and treatedwith a slight excess of ethereal hydrogen chloride to precipitate thehydrochloride salt which is recovered by filtration and recrystallizedfrom methanol-ether to give 1.57 g. of exo-6-methoxy-N,2,3,3-tetramethyl-ex0 2 norbornanamine, hydrochloride, m.p.253 C. (dec.).

Analysis.-Calcd. for C H NO'HCl: C, 61.65; H, 10.35; N, 5.99; Cl, 15.17.Found: C, 61.79; H, 10.78; N,

EXAMPLE Endo-6-meth0xy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XX) andthe hydrochloride salt thereof Following the procedure of Example 14,above 5.46 g. (0.02 mole) ofN-benzoyl-endo-G-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine(XVIII) is treated with 2.5 g. of aluminum isopropoxide and then with100' ml. of diazomethane solution to obtain N-benzyl-endo-6-methoxy-N,2,3,3 tetramethyl-exo-2-norbornanamine (XX), which is thenreduced with 4.0 g. of lithium aluminum hydride to give N-benzyl-endo 6methoxy-N,2,3,3-tetramethyl exo 2 norbornanamine (XXII). Compound (XXII)thus obtained is then reduced with hydrogen and 0.5 g. of palladium oncarbon catalyst to give endo-6- methoxy-N,2,3,3-tetramethyl-ex0 2norbornanamine (XXIV) as the free base, which is treated with etherealhydrogen chloride and recrystallized to give 2.21 g. ofena'0-6-methoxy-N,2,3,3 tetramethyl-exo-Z-norbornanamine, hydrochloride,m.p. 282 C. (dec.).

Analysis.-Calcd. for C H NOCl: C, 61.65 H, 10.35; N, 5.99; Cl, 15.17.Found: C, 62.07; H, 10.33; N, 6.28; Cl, 15.30.

EXAMPLE 16 Cis-7-methoxy-N,2,3,3-tetramethyl-ex0-2-norbornanamine (XXV)and the hydrochloride salt thereof Following the procedure of Example14, above 5.46 g. (0.02 mole) ofN-benzoyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine(compound XXIII). Comg. of aluminum isopropoxide and then with ml. ofdiazomethane solution to obtain N-benzoyl-cinJ-methoxy- N,2,3,3tetramethyl-exo 2 norbornanamine (XXI), which is then reduced with 4.0g. of lithium aluminum hydride to give N-benzyl-cis 7methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (compound XXIII).Compound (XXIII) thus obtained, is then reduced with hydrogen and 0.5 g.of palladium on carbon catalyst to give cis 7methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XXV) as the free base,which is treated with ethereal hydrogen chloride and recrystallized togive 2.09 g. (49% yield) of cis-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride, m.p. 282 C. (dec.).

Analysis.-Calcd. for C H NOCl C, 61.65; H, 10.35; N, 5.99; Cl, 15.17.Found: C, 61.71; H, 10.26; N, 6.34; Cl, 15.14.

EXAMPLE 17 Trans-7-methoxy-N-2,3,3-tetramethyl-exo-Z-norbornanamine(XXV) and the hydrochloride salt thereof Following the procedure ofExample 14, above 5.46 g. (0.02 mole) ofN-benzoyl-trans-7-hydroxy-N-2,3,3-tetramethyl-exo-Z-norbornanamine (XIX)is treated with 2.5 g. of aluminum isopropoxide and then with 100 ml. ofdiazomethane solution to obtainN-benzoyl-trans-7-methoxy-N,2,3,3-tetramethyl-ex0-2-norbornanamine(XXI), which is then reduced with 4.0 g. of lithium aluminum hydride togive N-benzyl-trans-7-methoxy-N,2,3,3-tetramethyl-ex'o 2 norbornanamine(XX'III). Compound (XXIII) thus obtained, is then reduced with hydrogenand 0.5 g. of palladium on carbon catalyst to give trans-7- methoxyN,2,3,3 tetramethyl-exo-2-norbornanamine (XXV) as the free base, whichis treated with ethereal hydrogen chloride and recrystallized to givetrans-7-methoxy-N,2,3,3 tetramethyl-ex0-2-norbornanamine, hydrochloride.

EXAMPLE 18 N-benzyl-ex0-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, tosylate A solution of 3 g. ofN-benzyl-exo-6-hydroxy-N,2,3,3- tetramethyl-exo-Z-norbornanamine (VII)in about 15 ml. of pyridine is treated with 4.0 g. of p-toluenesulfonylchloride at room temperature for about 22 hrs. The mixture is pouredonto 50 g. of ice and stirred. The aqueous phase is decanted from theoily product which is washed twice with water by stirring anddecantation. About 2.0 ml. of methanol is then added and the oil iscrystallized. The product is recovered by filtration and washed with alittle cold methanol to give 3.40 g. of N-benzyl-ex0-6- hydroxy-N, 2,3,3tetramethyl-exo 2-n0rbornanamine, tosylate, m.p. 62-66" C.; ananalytical sample is obtained by recrystallization from methanol, m.p.67-69 C.

Analysis.--Calcd. for C H NO S: C, 70.22; H, 7.78; N, 3.28; S, 7.50.Found: C, 70.19; H, 7.94; N, 3.19; S, 7.81.

EXAMPLE 19 N-benzyl-end0-6-hydroxy-N,2,3,3-tetramethyl-ex0-2-norbornanamine, tosylate Following the procedure of Example 4, above,1.17 g. of N-benzyl-endo 6-hydroxy-N,2,3,3-tetrahydro-ex0-2-norbornanamine (VI) in about 5 ml. of pyridine is treated with 1.5 g. ofp-toluenesulfonyl chloride to obtain 1.4 g. of N-benzyl-endo6-hydroxy-N,2,3,3-tetramethyl-ex0-2- norbornanamine, tosylate, m.p.116-117 C.

AnaZysis.-Calcd. for C H NO S: C, 70.22; H, 7.78; N, 3.28; S, 7.50.Found: C, 70.34; H, 7.81; N, 3.18; S, 7.38.

EXAMPLE 20 N-benzyl-cis-7-hydroxy-N-2,3,3 -tetramethyl-ex-2-norbornanamine, tosylate Following the procedure of Example 4, above,3.67 g. ofN-benzyl-cis-7-hydr0xy-N,2,3,S-tetramethyl-exo-Z-norbornanamine (XI) inabout 20 ml. of pyridine is treated with 5.0 g. of p-toluenesulfonylchloride to obtain 3.34 g. ofN-benzyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine,tosylate, m.p. 124-126 C.

Analysis.Calcd. for C H NO S: C, 70.22; H, 7.78; N, 3.38; S, 7.50.Found: C, 69.96; H, 7.85; N, 3.45; S, 7.38.

EXAMPLE 21 N-benzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, tosylate Following the procedure of Example 4, above,3.67 g. of N-benzyl-trans 7-hydr0Xy-N,2,3,3-tetramethyl-ex0-2-norbornanamine (XII) in about 20 ml. of pyridine is treated with 5.0 g.of p-toluenesulfonyl chloride to obtain N-benzyl-tmrzs 7 hydroxy-N,2,3,3tetramethyl-ex0-2- norbornanamine, tosylate.

What is claimed is:

1. A compound of the formula A, B, C or D:

CH CH N-R R CH3 CH2 CH CH A 3 s s liSH CH3 N-R N-R CH3 CH3 CH CH i\ CH3CH3 wherein R is benzoyl and R and R are each hydroxy or methoxy.

2. A compound of the formula:

wherein R is benzoyl; and R is hydroxy or methoxy.

3. A compound of the formula:

wherein R is benzoyl; and R is hydroxy or methoxy.

4. A compound of the formula:

wherein R is benzoyl; and R is hydroxy or methoxy.

5. N benzoyl exo 6 hydroxy N,2,3,3 tetramethyl-exo-Z-norbornanamine, thecompound of claim 2 wherein R is benzoyl and R is hydroxy.

6. N benzoyl exo 6 methoxy N,2,3,3 tetramethyl-exo-2-norbornanamine, thecompound of claim 2 wherein R is benzoyl and R is methoxy.

7. N benzoyl endo 6-hydroxy N,2,3,3 tetramethyl-exo-2-norbornanamine,the compound of claim 3 wherein R is benzoyl and R is hydroxy.

8. N lbenzoyl enldo 6 methoxy N,2,3,3 tetramethyl-exo-Z-norhornanamine,the compound of claim 3 wherein R is benzoyl and R is methoxy.

9. N benzoyl cis 7 hydroxy N,2,3,3 tetramethyl-exo-Z-norbornanamine, thecompound of claim 4 wherein R is benzoyl and R is hydroxy.

10. N benzoyl cis 7 methoxy N,2,3,3 tetramethyl-exo-Z-norbornanamine,the compound of claim 4 wherein R is benzoyl and R is methoxy.

11. N benzoyl 6 keto N,2,3,3 tetramethyl exo- 2-norbornanamine.

12 N benzoyl 7 keto N,2,3,3 tetramethyl ex0- 2-norbornanamine.

References Cited Herr et aL: J. Med. Chem, vol. 14, pp. 842-45 (1971).

HARRY I. MOATZ, Primary Examiner US. Cl. X.R.

-51 R; 260-456 P, 468 R, 476 R, 485 L, 486 R, 488 CD, 570.9, 584 R;424-324 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,847,982 Dated November 12, 1974 Invent r( MI I ton E. Herr, Herbert C.Mu rphv, Gunther S Fonken It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 7, l Ines 9-10, hydroxylamines" should read hydroxybenzylaminesColumn 8, line 13, (X), (XII) and" should read (x), (XI), (XI l) andColumn 9,-line 403 should read (I I), Column 12, line 67, "(XVI shouldread (XIV) Column 15, line 1, '-bornanamine" should read -norbornanamineColumn 14, lines 13-14,

"(compound XXI I I). Com.- 9. of" should read -r (XIX) is treated with2.. 5 g. of Column 15, l ine 18, "N, 5.38;

should read N, 5.28;

Signal and Sealed this second D 3} Of A ugusl I977 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Arresting ff Commissioner of Patents andTrademarks

1. A COMPOUND OF THE FORMULA A, B, C OR D: